Pilot studies of the clinical efficacy, toxicity, and immunological effects of halogenated adenosine analogs, such as fludarabine and chlorodeoxyadenosine, are being studied in patients with several autoimmune disorders. These agents primarily affect lymphoid cells because only these cells contain substantial amounts of the enzymes necessary for activation of the adenosine analogs. Previous investigations employing these drugs in patients with low grade lymphoid malignancies have shown that they selectively target immune cells by inducing apoptotic cell death. Their effects on the clinical course of non-malignant, immunologic diseases, as well as on the function of immune cells have not been characterized. The present project involves study of eight patients to date who have been entered into a pilot trial of low-dose fludarabine treatment for refractory forms of membranous nephropathy. No major or unexpected toxicities have been encountered. Fludarabine treatment has resulted in sustained B and T lymphopenia (B>T). CD3, CD4, CD8 and B cell counts decreased by 53%, 46%, 61% and 84% at the end of treatment and remained at lower than pretreatment levels 6 months after completing the fludarabine treatments. We are attempting to determine whether the level of lymphopenia should be a major determinant of safe drug doses; no substantive changes in total immunoglobulin or antibody levels have been seen. At the low doses of fludarabine used thus far, two patients have had a significant decrease in proteinuria. We intend to evaluate whether escalation of fludarabine dosage will further enhance efficacy in autoimmune conditions.